COGNITIVE AND NEUROPSYCHOLOGICAL

ASSESSMENTS FOR CO-OCCURRING OPIOID

AND AMPHETAMINE-TYPE STIMULANT

(COATS) DEPENDENT PATIENTS

NORHAMIZAH BINTI HASHIM

UNIVERSITI SAINS MALAYSIA

2016

COGNITIVE AND NEUROPSYCHOLOGICAL

ASSESSMENTS FOR CO-OCCURRING OPIOID

AND AMPHETAMINE-TYPE STIMULANT

(COATS) DEPENDENT PATIENTS

By

NORHAMIZAH BINTI HASHIM

Thesis submitted in fulfillment of the requirements for

Degree of (Master of Clinical Science)

December 2016

ii

ACKNOWLEDGEMENT

First of all, I would like to thank and express my gratitude to Allah S.W.T for

giving me strength in completing this dissertation successfully.

A special thanks goes to my principal supervisor, Dr. Chooi Weng Tink, and

my co-supervisor Associate Professor Dr. Norzarina Binti Mohd Zaharim for their

assistance, support and supervision given throughout this research.

I’m also indebted to Associate Professor Dr. B. Vicknasingam for giving me an

opportunity to be involved in this drug addiction study area by providing grant

(1001/CDADAH/852003 and 304/CDADAH/650628) to conduct this research. Also, I

would like to acknowledge University Science Malaysia Fellowship Scheme for the

financial support.

My sincere thanks also go to my friends who helped me throughout this

research. I would like to express my deepest appreciation to my parents, husband and

my only daughter for their endless moral support from the beginning until the end of

this study.

Thank you

iii

TABLE OF CONTENTS

ACKNOWLEDGEMENT ii

LIST OF FIGURE viii

LIST OF TABLES ix

LIST OF ABBREVIATIONS x

ABSTRAK xi

ABSTRACT xii

CHAPTER 1 : INTRODUCTION

1.1 Background Of The Study 1

1.2 Opioid 2

1.3 Amphetamine-Type-Stimulants 3

1.4 Co-Occurring Opioid and Amphetamine Type Stimulants (COATS) 5

1.5 Addiction and Cognition 6

1.6 Cognitive Deficit Model 8

1.7 Amphetamine and Opioids Cognitive Deficit 8

1.8 Problem Statement 9

1.9 Objectives of the Study 11

1.10 Hypotheses 11

1.11 Significance of the Study 13

1.12 Scope of the Study 14

1.13 Study Limitations 15

1.14 Definition of Terms 15

1.14.1 Opioid 15

1.14.2 Amphetamine-Type Stimulants 16

1.14.3 Co-Occurring Opioid and ATS 16

1.14.4 Cognitive Psychology 16

1.14.5 Neuropsychological Assessment 16

1.14.6 Memory 17

1.14.7 Attention 17

1.14.8 Visual Scanning 17

1.14.9 Mental Processing Speed 18

Page

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1.14.10 Working Memory 18

CHAPTER 2 : LITERATURE REVIEW

2.0 Introduction 19

2.1 Drug Addiction 19

2.2 Opioid 21

2.3 Amphetamine Type Stimulants 22

2.4 Co-occurring Opioid and ATS Use 22

2.5 Neuronal Structure 24

2.5.1 Brain 24

2.5.2 Nerve Cell 25

2.5.3 Neurotransmitters 26

2.6 Substance Dependency and the Brain 26

2.7 Cognitive Deficits in Chronic Drug Use 27

2.7.1 Opioids 27

2.7.2 Amphetamine 29

2.8 Neuropsychological Tests 31

2.9 Executive Function 32

2.9.1 Inhibitory Control 32

2.9.2 Working Memory 33

2.10 Drug Use Trend in Kelantan 34

2.11 Medication-Assisted Treatment 34

2.12 Possible and Available Treatment for Cognitive Deficits 35

2.12.1 Cognitive Training and Rehabilitation 35

2.12.2 Pharmacological Treatments 36

2.13 Theoretical and Conceptual Framework 38

CHAPTER 3 : METHODOLOGY

3.1 Research Design 40

3.2 Sample Size and Sampling Technique 40

3.3 Study Procedure 41

3.4 Study Location 42

3.5 Psychometric Theory 42

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3.6 Inclusion and Exclusion Criteria 43

3.6.1 Inclusion Criteria 43

3.6.2 Exclusion Criteria 43

3.7 Study Instruments 43

3.8 Measures 44

3.8.1 Rey-Osterrieth Complex Figure (ROCF) 44

3.8.2 Trail Making Test (TMT) 45

3.8.3 RAVENS Progressive Matrices 46

3.8.4 Digit Span Test (DST) 46

3.8.5 Symbol Digit Test (SDT) 47

3.8.6 Stroop Test 48

3.9 Translation of Instrument 49

3.10 Pilot Study 49

3.11 Statistical Analysis 49

3.11.1 Normality Distribution 49

3.11.2 Statistical Tests 50

CHAPTER 4 : RESULTS

4.1 Participants 51

4.2 Socio-demographic Characteristics 51

4.2.1 Age, Gender and Ethnicity 51

4.2.2 Education 51

4.2.3 Employment 52

4.2.4 Income 52

4.3 Duration of Drug use in DDD patients 52

4.4 Normality Distribution for All Test Batteries 54

4.5 Cognitive Test Result 69

4.5.1 Rey-Osterrieth Complex Figure (ROCF) Result 69

4.5.2 Trail Making Test (TMT) Result 69

4.5.3 RAVENS Progressive Matrices Result 70

4.5.4 Digit Span Test (DST) Result 70

4.5.5 Symbol Digit Test (SDT) Result 70

4.5.6 Stroop Test Result 70

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4.6 Summary of the Test Results 71

CHAPTER 5 : DISCUSSION AND CONCLUSION

5.1 Introduction 72

5.2 Cognitive Test Result of Study Group 72

5.2.1 ROCF 72

5.2.2 Trail Making Test A and B 73

5.2.3 Ravens Progressive Matrices 73

5.2.4 Digit Span Test (DST) 74

5.2.5 Symbol Digit Test (SDT) 74

5.2.6 Stroop Test 75

5.3 Recommendation 75

5.3.1 Neuroimaging Study 75

5.3.2 Cognitive Training and Rehabilitation 76

5.3.3 Pharmacological Treatment 77

5.4 Limitations of the Study 77

5.5 Conclusion 77

REFERENCES 80

APPENDICES

vii

LIST OF FIGURE

Page

Figure 1.1 Heroin Powder and Common Route of Administration 3

Figure 1.2 ATS tablet that commonly used in Kelantan region 5

Figure 1.3 Mesolimbic Reward System 8

Figure 2.1 Albert Bandura’s Theory 38

viii

LIST OF TABLES

Page

Table 2.1 Part of brain and its function 25

Table 4.1 Sociodemographic Characteristic of Study Group 53

Table 4.2 Summary of Statistical Analysis for all cognitive measures 68

ix

LIST OF ABBREVIATIONS

DDD Dual Drug Dependence

HIV Human Immunodeficiency Virus

ATS Amphetamine Type Stimulants

UNODC United Nation of Drug and Crime

MA Methamphetamine

UNODC United Nation on Drug and Crime

ROCF Rey-Osterrieth Complex Figure

TMT Trail Making Test

DST Digit Span Test

SDT Symbol Digit Test

VTA Ventral Tegmental Area

DA Dopamine

NAC Nucleus Accumben

PFC

NIDA

CBT

Prefrontal Cortex

National Institute of Drug Abuse

Cognitive Behavioral Therapy

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PENILAIAN KOGNITIF DAN NEUROPSIKOLOGIKAL DALAM

KALANGAN PESAKIT YANG ADA DWI-KEBERGANTUNGAN

TERHADAP OPIOID DAN PERANGSANG JENIS AMFETAMINA (COATS)

ABSTRAK

Kajian menunjukkan individu yang ada kebergantungan terhadap dadah

mempunyai fungsi kognitif yang lebih rendah dalam domain fungsi eksekutif. Kajian

yang melibatkan pengguna dadah yang menggunakan beberapa jenis dadah adalah

terhad. Kajian ini direka bentuk untuk menilai skop dan corak spesifik masalah

kefungsian kognitif dan neuropsikologikal dalam kalangan individu yang

menyalahgunakan opioid dan ATS (dwi-kebergantungan (DDD)) dan memasuki

rawatan bantuan ubatan di Hospital Universiti Sains Malaysia (HUSM), Kelantan.

Sejumlah n=96 responden lelaki (n=56 pesakit dan n=40 kumpulan kawalan) telah

diambil untuk kajian rentas ini. Ujian neuropsikologikal Rey Osterrieth Complex

Figure, Trail Making Test, Raven’s Progressive Matrices, Digit Span Test, Digit

Symbol Test, and Stroop Test telah dilakukan. Keputusan kajian menunjukkan prestasi

pesakit adalah lebih rendah daripada prestasi kumpulan kawalan dalam kelajuan

persepsi motor dan imbasan visual yang diukur menggunakan Trail Making Test Part

A, dalam fleksibiliti kognitif yang diukur menggunakan Trail Making Test Part B dan

dalam kelajuan pemprosesan mental yang diukur menggunakan Digit Symbol Test.

Keputusan menunjukkan ada sedikit gangguan dalam kelajuan persepsi motor, imbasan

visual, fleksibiliti kognitif dan kelajuan pemprosesan mental dalam kalangan pesakit

yang ada dwi-kebergantungan. Oleh itu, intervensi pencegahan dan rawatan yang baik

perlu mengambil kira masalah kognitif dalam kalangan pesakit yang ada dwi-

kebergantungan.

xi

COGNITIVE AND NEUROPSYCHOLOGICAL ASSESSMENTS

AMONG CO-OCCURRING OPIOID AND AMPHETAMINE-TYPE

STIMULANT (COATS) DEPENDENT PATIENTS

ABSTRACT

Several studies have shown that individuals with drug dependence have poorer

cognitive functions in the domain of executive functions. Studies investigating

cognitive impairments in people with poly-drug use are limited. This study is designed

to evaluate the scope and the specific patterns of deficits in cognitive and

neuropsychological functioning among opiate and ATS (Dual Drug Dependence

(DDD)) abusing individuals enrolled in a medication-assisted treatment in Hospital

Universiti Sains Malaysia (HUSM), Kelantan. A total of n=96 male respondents (n=56

patients, and n=40 control group) were recruited for this cross-sectional study.

Cognitive functions evaluated were Rey-Osterrieth Complex Figure, Trail Making

Test, Raven’s Progressive Matrices, Digit Span Test, Digit Symbol Test, and Stroop

Test were administered. Results showed that patients performed significantly worse in

perceptual motor speed and visual scanning measured by Trail Making Test Part A,

cognitive flexibility measured by Trail Making Test Part B, and mental processing

speed measured by Digit Symbol Test compared to those in the control group. Results

suggest that there were slight impairments in perceptual motor speed, visual scanning,

cognitive flexibility, and mental processing speed among patients with dual drug

dependence. Therefore, proper prevention and treatment interventions should take into

account the cognitive problems in patients who have dual dependency.

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CHAPTER 1

INTRODUCTION

1.1 Background Of The Study

Drug addiction continues to be a global rampant problem. According to

National Institute of Drug Abuse (2014), addiction is a relapsing disease characterized

by intense drug seeking behavior and use of drug accompanied by chemical changes in

brain Malaysia is also no exception in this problem. In Malaysia, heroin continues to

be the main drug used whereas amphetamine-type stimulants use is increasing (Singh,

Chawarski, Schottenfeld, & Vicknasingam, 2013). The drug users that were detected

between 1988 and 2006 were 300,241. It is also estimated that Malaysia has 170,000

injecting drug users who also have Human Immunodeficiency Virus (HIV) and the

prevalence among drug users in the country ranges from 25% to 45% (Singh et al.,

2013).

Recently, amphetamine-type stimulants (ATS), including crystal

methamphetamine and various other methamphetamine and/or amphetamine-

containing substances/pills, have been identified as a growing problem, not only in

Malaysia but also throughout the Southeast Asia Region (Mcketin, Kozel, & Douglas,

2008). Although much research has been done on drug addiction in Malaysia, the

cognitive and neuropsychological aspects of drug use remained scarce (Zamani, Nasir,

Desa, Khairudin, & Yusooff, 2014).

2

1.2 Opioid

Opioid is usually used in medicine for pain relief. But misuse of opioid may

lead to many withdrawal symptoms such as restlessness, weakness, chills, body and

joint pain, social withdrawal and many more. There has been little study on

neurocognitive effects by heroin pure users. Opioids, namely heroin and illicit

morphine, continued to be the most widely used drugs in Malaysia (United Nation

Office on Drugs and Crime, 2013). Heroin remains the primary drug used in Malaysia.

In 2012, approximately 48% of all drug users had used heroin while 31% had used illicit

morphine (Malaysia Country Report, 2013). A large portion of heroin seized in

Malaysia is originated from Myanmar and is trafficked overland through Thailand

(Malaysia Country Report, 2013). Malaysia has been involved in drug abuse problems

since the 1970s, and the major driver of HIV transmission in Malaysia is causing by

drug abuse (Chawarski, Vicknasingam, Mazlan, & Schottenfeld, 2012).

Heroin is extracted from the poppy plant. It is characterized as a white powder

with a bitter taste. Pure heroin can be either smoked or inhaled. The short term effect

of heroin is being in a pleasurable sensation due to the activation of brain reward system

and this may last for a few hours, thus, individual must take it repeatedly and lead to

addiction (National Institute of Drug Abuse, 2010). Long term effect and repeated use

of heroin can change physiology and neuronal imbalance in brain and aid to physical

dependence on this drug (NIDA, 2014)

Withdrawal symptoms such as muscle pain, insomnia, restlessness, bone pain,

and many more occur when one stops using heroin. Addiction to heroin may bring the

individual to put the use of this drug are main purpose of life. But, there are several

medications that are recommended for detoxification from heroin such as Methadone

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and Buprenorphine (Whelan & Remski, 2012). Also, some cognitive behavioral

therapies (CBT) are recommended as part of treatment. CBT is the process of

identifying negative pattern of thought which will influence one’s behavior. The

negative thought patterns always play a main role in development of addiction

(Kimmel, 2015). Examples of CBT techniques used in addiction treatment include

pleasant activity schedule which may help recovering addict to make a healthy weekly

list including fun activities that may break up daily routines. This may help reduce

negative automatic thoughts and the subsequent need to use drug. (Addiction Center,

2015).

Figure 1.1: Heroin Powder and Common Route of Administration Using

Syringe

1.3 Amphetamine-Type-Stimulants

Amphetamine and methamphetamine are from the group of psycho-stimulants

where the methamphetamine is a synthetic derivative of amphetamine. Because of the

chemical structure of methamphetamine, it has high lipid solubility compared to

amphetamine and thus, it has intense effect on central nervous system. ATS is a group

of drugs whose principal members are amphetamine and MA. The use of ATS has

4

become a part of the mainstream culture in many countries and has become a worldwide

problem in the recent years (United Nation of Drug and Crime, 2009). According to the

United Nation on Drug and Crime (UNODC), ATS has become the world’s second

most widely abused drug type after cannabis (UNODC, 2011). The geographical spread

is widening, but awareness of it is limited. There are urgent needs to study about ATS

problem because the higher usage may increase the level of presentation of ATS

psychosis to mental health service (World Health Organization, 2015)

The trafficking of ATS to Malaysia for both domestic use and as a transit

location for international markets remains a problem (UNODC, 2013). ATS continued

to be the most commonly used drug among new drug users and drug users arrested for

the first time (UNODC, 2013). More recently, ATS including crystal methamphetamine

and various other methamphetamine and/or amphetamine containing substances or

pills, have been identified as a growing problem in Malaysia and throughout East and

South-East Asia (McKetin et al., 2008; Sutcliffe et al., 2009; UNODC, 2011).

UNODC’s 2010 estimated that up to 20.7 million individuals in Asia and the Pacific

have used ATS in the past years (Global SMART Programme, 2010). A study done by

Vicknasingam et al., (2010) found that in many regions of Malaysia, most of opioid

Injecting Drug Users individuals use ATS during their lifetime.

Amphetamine also can affect the capacity of brain to stimulate neurogenesis

(growth and development of nervous tissue) and this could cause the disruption of

Blood-brain barrier (BBB) (Silva et al., 2010). The chronic effects of amphetamine

(psychostimulatory effect) not only connected with reward and euphoria, but the effects

are including impairment in attention and memory. Thus, this cognitive effect related

to neurotoxic effect of drug and apoptosis (Krasnova, Ladenheim, & Cadet, 2005).

5

Amphetamine in acute phase may inhibit the reuptake of Dopamine,

Norepinephrine, and Serotonin by membrane transporters and increase this level of this

neurotransmitter in the brain and it will then result in depletion of dopamine transporter

and this will give impairment in their neuropsychological functioning (Logan, 2002;

Camí, & Farré, 2003; Nordahl, Salo, & Leamon, 2003; Fernández-Serrano, Pérez-

Garcia, & Verdejo-Garcia, 2011).

Figure 1.2: ATS tablet that commonly used in Kelantan region

1.4 Co-Occurring Opioid and Amphetamine Type Stimulants (COATS)

The use of two or more substances at the same time and sequentially are

considered as a poly-drug use. There are various patterns that can be seen, one of the

patterns was different substances being taken together to have a cumulative or

complementary effect (UNODC, 2014).

ATS is a stimulant whereas heroin is a depressant. The combination of these

drugs have become more frequent and popular among drug users (Singh et al., 2013).

A new trend of dual-dependence (Opioid and ATS) provides the baseline information

regarding the need to implement the effective treatment approach (Singh et al, 2013).

The effective treatments include medication therapy and psychological aspect such as

6

counseling. Cognition is the central of drug addiction thus, it is important to conduct

research that evaluates cognition and one of the tests that can be used to measure it was

neuropsychological assessment.

The simultaneous use of stimulants and opioids has, for over a century, have

been reported to be a superior combination for pain relief. Besides, it is perceived that

the endogenous endorphin-opioid receptor system is the only pain control mechanism

in the central nervous system. In reality, multiple neurochemical systems are at play in

pain relief. They include, among others, the serotonergic, gamma-amino-butyric acid

(GABA-ergenic), and adrenergic (norepinephrine-dopamine) systems. Pain relief with

stimulants appears to be primarily mediated by norepinephrine and not dopamine. It is

the simultaneous triggering of the endorphin and adrenergic neurochemical systems

that gives the combined administration of opioids and stimulants a pain-relieving effect

much greater than either one alone.

1.5 Addiction and Cognition

Cognitive impairment is when a person has trouble remembering, learning new

things, concentrating, or making decisions that affect their everyday life. Chronic use

of heroin and morphine may lead to various cognitive impairments (Spain & Newsom,

1991; Hauser, Houdi, Turbek, Elde, & Ili, 2000; Yin, Woodruff, Zhang, Whaley, Miao,

& Ferslew, 2006). The consequence of damaging cognitive function will give the

negative impact to their thinking and memory process that could lead to mental illness

and ineffective treatment approach

There are widespread deficits in neuropsychological function associated with

chronic use of psychoactive substance (Verdejo-Garcia et al, 2004; Ornstein, Iddon,

Baldacchino, Sahakian, London, Everitt, & Robbins, 2000). From the neurological and

7

psychological perspectives, addiction may cause disorders or alteration in cognition.

Drugs alter normal brain structure and function in regions that are responsible for

controlling cognitive functions such as learning, attention, memory, and impulse

control. This will promote continues of drug use and will hinder the treatment process

that support sustained abstinence.

Numerous studies found that individuals who use drugs usually have alteration

in the prefrontal cortex (Kelley, 2004; Kalivas & Volkow, 2005; and Lemoal & Koob,

2007). There are many factors that influence whether a particular person who takes and

experiments with opioid drug will continue taking them for a longer time to become

dependent or addicted. Opioid may provide intense feeling of pleasure.

Heroin or other opioid can cross the blood brain barrier and thus, travel through

bloodstream in the brain. The chemical will then be attached to specialized proteins

called mu receptors on the brain cell. Linkage between this chemical and receptor will

trigger biochemical brain process and the reward system is activated and they feel

pleasure. This opioid may activate brain circuit that we call mesolimbic (midbrain)

reward system. This system then will generate the signal in a part of brain that we call

ventral tegmental area (VTA) that will result the release of dopamine (DA) in another

part of brain, the nucleus accumbens (NAc- brain key pleasure centre). The release of

DA to NAc will cause the feeling of pleasure. The opioid stimulation of brain’s reward

system is the main reason why some people take drugs repeatedly. Repeated exposure

of opioid drugs may induce brain mechanism of dependence and lead to daily drug use

to alleviate withdrawal symptoms.

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Figure 1.3: Mesolimbic Reward System (Kosten, & George, 2002)

1.6 Cognitive Deficit Model

This model states that a person who develops addictive disorder may have

abnormalities in an area in brain called the prefrontal cortex (PFC). PFC is important

for regulation of judgment, planning, and other executive functions. This model also

proposes that PFC signals to mesolimbic reward system are compromised in individuals

with addictive disorders and as a result, the ability to use judgments to restrain their

impulses is reduced and leads to a predisposition to compulsive drug-taking behavior.

Consistent with this model, stimulant drugs such as ATS is suggested to damage the

fronto-striatal loop that carries inhibitory signal from PFC to mesolimbic reward

system. (Kosten & George, 2002)

1.7 Amphetamine and Opioids Cognitive Deficit

Both amphetamine and opioid may activate dopamine system in midbrain which

associated with positive reinforcing effect and have addictive potential. But, both

pharmacological effects are different. There are studies on comparison of psycho-

stimulant drug and opioids and most of the studies were conducted with participants in

treatment settings (Fernández-Serrano, Pérez-García & Verdejo-García, 2011).

9

A study performed by Ornstein et al. (2000) that evaluated cognitive functions

among amphetamine or heroin were compared, together with age- and IQ-matched

control subjects showed deficit in a range of cognitive skills, including pattern

recognition, planning and ability to shift attention from one frame of reference to

another. This study suggested chronic drug use may lead to distinct patterns of cognitive

impairment that may be associated with dysfunction of different components of cortico-

striatal circuitry. Additionally, Ersche and colleague (2006) found that chronic drug

users display neuropsychological impairment in executing function and memory also,

if the impairment persist after several years, it may reflect neuropathology in frontal

and temporal cortices.

The chronic effects of prolonged substance abuse may differ between opiate and

amphetamine supported by a study of examination of post-mortem of brain indicate

amphetamine users qualitatively obtain more severe neuropathology compared to

opiate users (Kish et al., 2001). Even though there are neuropathology studies regarding

effect of amphetamine and opioid users respectively, neuropsychological studies that

directly compare the cognitive performance in both amphetamine and opiate users are

still sparse (Ersche et al., 2006).

1.8 Problem Statement

Having stimulant and hallucinergic effects, ATS has a wide range of physical

and psychological health impact. Long term of the use of both substances may lead to

various cognitive impairments. Dependence on opioid and ATS frequently co-occur,

and many studies showed that cognitive impairment as a result of using this drug

(Pilowsky, 2011).

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However, studies about cognitive function for drug user that use both drugs are

scarce. Based on the study done by Dalleys et al. (2005), they found that most

amphetamine users have deficit in cognitive especially in their attention. Other than

that, one of the studies done by Hekmat et al. (2010) found that the addicted subject in

performing heroin is worse in executive function measures such as speed of mental

processing measured by digit symbol test. The trend of using this both drugs together

are keep increasing, thus the cognitive measure may provide a clear picture and will aid

in treatment programs for drug users.

Kelantan was experiencing serious problem with opioid, ATS and HIV

compared to other state of Malaysia. The number of ATS-related arrests in Kelantan

increased 5051 substantially from 2,900 in 2007 to 5,300 in 2010 and 9,413 in 2012

(Royal Malaysian Police 2013). According to AADK report, the statistic of a new drug

users in Kelantan was increased from 1019 (7.49%) in 2014 to 1683 (8.30%) in 2015

(AADK, 2014, 2015). Besides, there was also increased in registered new drug users

from 29 269 in 2014 to 31 257 in 2015 based on AADK current report.

Co-occurring ATS and Opioid are quite concerning in Kelantan. Both types of

drugs are highly addictive, and it overlapping effect on brain reward system and

circulatory that regulating motivation, emotional and executive function including

impulse control (Ersche & Sahakian 2007; Trujillo, Smith & Guaderrama 2011). Other

than that, the person that using both drug (ATS and Opioids) usually having high level

of psychiatric co-morbidity and require more intensive clinical management (Pilowsky

et al. 2011).

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1.9 Objectives of the Study

To evaluate the scope and the specific patterns of deficits in cognitive and

neuropsychological functioning among opiate and ATS (Dual Drug Dependence

(DDD)) abusing individuals enrolled in a medication-assisted treatment in Hospital

Universiti Sains Malaysia (HUSM) with a healthy control group in Kelantan. Cognitive

functions evaluated were:

1. Visuo-constructional, visuo-perceptual ability, incidental visual memory and

attention - Rey-Osterrieth Complex Figure (ROCF).

2. Perceptual Motor Speed, Visual Scanning and Cognitive Flexibility - Trail

Making Test Part A and B

3. Reasoning Skills - Raven’s Progressive Matrices.

4. Short-term Memory and Working Memory - Digit Span Test Forward and

Backward (DST).

5. Speed of Mental Processing - Symbol Digit Test (SDT).

6. Response Inhibition - Stroop test.

1.10 Hypotheses

1. H0 - There is no significant mean difference in visuo-constructional, visuo-

perceptual ability, incidental visual memory and attention between Dual Drug

Dependence (DDD) patients and control group measured by Rey-Osterrieth

Complex Figure (ROCF).

H1–There is a significant mean difference in visuo-constructional, visuo-

perceptual ability, incidental visual memory and attention between (DDD)

patients and control group measured by Rey-Osterrieth Complex Figure

(ROCF).

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2. H0 - There is no significant mean difference in Perceptual Motor Speed, Visual

Scanning and Cognitive Flexibility between DDD patients and control group

measured by Trail Making Test Part A and B.

H1 – There is a significant mean difference in Perceptual Motor Speed, Visual

Scanning and Cognitive Flexibility between DDD patients and control group

measured by Trail Making Test Part A and B.

3. H0 - There is no significant mean difference in reasoning skills, between DDD

patients and control group measured by Raven’s Progressive Matrices.

H1 - There is a significant mean difference in reasoning skills, between DDD

patients and control group measured by Raven’s Progressive Matrices.

4. H0 - There is no significant mean difference in short-term memory and working

memory between DDD patients and control group measured by Digit Span Test

Forward and Backward (DST).

H1 - There are significant mean differences in short-term memory and working

memory between DDD patients and control group measured by Digit Span Test

Forward and Backward (DST).

5. H0 - There is no significant mean difference in speed of mental processing

between DDD patients and control group measured by Symbol Digit Test

(SDT).

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H1 - There are significant mean differences in speed of mental processing

between DDD patients and control group measured by Symbol Digit Test

(SDT).

6. H0 - There is no significant mean difference in response inhibition between

DDD patients and control group measured by Stroop test.

H1 - There are significant mean differences in response inhibition between DDD

patients and control group measured by Stroop test.

1.11 Significance of the Study

This study is about cognitive and neuropsychological functioning of opioid and

ATS use and it provides cognitive profile (executive functions) with the emphasis on

visuo-perceptual, visuo-constructional ability, incidental visual memory, attention,

perceptual motor speed, visual scanning, cognitive flexibility, reasoning skills, short

term memory, working memory, speed of mental processing and response inhibition.

This study is expected to provide an insight about possible cognitive impairments

related to the use of both drugs since this is the first known study to measure cognitive

function among drug addicts that use both drugs in Malaysia. Besides, this study also

provides data on cognitive function of heroin and ATS users.

It is important in considering the present cognitive function when treating

patient with addiction. This could enable clinicians to help patients to master adaptive

strategies in overcoming patient relapse when patient return to the environments related

with their prior use of drug. Besides, cognitive deficit may hinder patient’s ability to

maximize benefits from counseling session and other psycho-social treatments in aiding

the patient to stay abstinent from drug use by learning or incorporating sustaining

14

strategies in their daily routine (Gould, 2010). Evidence showed that cognitive

impairment in drug use has negative impact especially in treatment engagement (Ersche

& Sahakian, 2007).

1.12 Scope of the Study

This study was carried out in Kelantan (Kota Bharu) because heroin and ATS

dependence are highly prevalent and frequently co-occur (Singh et al., 2013). This

region has high concentrated amount of individuals who use drugs and the trend of

using both drugs is increasing. Also, Kelantan has the highest number of HIV case in

Malaysia (Utusan Malaysia, 2015). The study focus on cognitive function that may

impair DDD patients by using selected neuropsychological test.

Neuropsychological tests are used to study a range of cognitive skills in

different areas. Neuropsychological testing is a crucial part of assessment and treatment

of patients especially patients with brain problem and it is also beneficial to investigate

substance use effects on brain functioning (Barry & Carson-DeWitt, 2005). This test is

used for screening to know if diagnostic assessments are needed or not.

Six neuropsychological test was used in this study to the COATS patient and

control healthy group. For the population, this study focus on two group, which are

DDD patient who dependence on ATS and Opioid and one control healthy group. This

study was conducted to determine the cognitive status of COATS patient and

comparing with control group. COATS patient that was recruited in this study was from

medication assisted treatment (treatment that combine medication and psychological

aspect) in HUSM. The aspects looked into were the neurocognitive functioning among

COATS patient. For the control group, the test was similar used by COATS patients

and also the place of assessment also the same. The problem was identified to provide

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better treatment by recognizing their impairment comparing with the normal control

group who did not use any illegal drug and identifying the proposed solution to the

problem. The location of the study was at HUSM.

1.13 Study Limitations

There were some unavoidable limitations. For this study, it was conducted in

only one state in Malaysia (Kelantan), and thus should not be generalized to the whole

issue of drug use in the country. It was important to do this study in every part of

Malaysia to see the clear picture on drug addiction cognitive profiles crucially. Thus,

in the future, these types of study can be done in every part of the state in Malaysia with

the convenient drug detoxification facility to address their cognitive deficit.

Other limitation was the number of COATS patient was small. In order to get

better result higher number of patient are required. The problem encountered was, the

COATS patients was a hidden population, hard to get reach to their area. But with the

amount of COATS patient we get are enough to run the analysis. In future, getting more

participant may give concrete result. Nevertheless, for the control group, easy to get the

involved in this study because easy recruiting them because they was not a hidden

population.

1.14 Definition of Terms

1.14.1 Opioid

Opioid are mainly used to relieve pain. It will reduce the intensity of the pain when

the signal of pain reaching the brain and it will diminished the painful effects stimulus (NIDA,

2014). Opioids are chemically interacted with opioid receptors in the nerve cells especially in

the body and brain. Misuse of opioid may lead to euphoria instead of pain relievers. Misuse of

opioid also can lead to drug dependence and fatal if overdose (NIDA, 2014).

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1.14.2 Amphetamine-Type Stimulants

Amphetamine-type stimulants (ATS) refer to a group of drugs whose

principal members include amphetamine and methamphetamine. However, a

range of other substances also fall into this group, such as methcathinone,

fenetylline, ephedrine, pseudoephedrine, methylphenidate and MDMA or

‘Ecstasy’ – an amphetamine-type derivative with hallucinogenic properties

(WHO, 2016).

1.14.3 Co-Occurring Opioid and ATS

Co-occurring define as a ‘to appear together’. In this context, co-occurring

refer to person that take both opioid and ATS simultaneously to get pleasurable

effect. The use of this both drug will increased the pleasurable effect uniquely

such as reduce anxiety, that was experienced by ATS or reduces sedation which

experienced by opioid, compared if using it alone (Leri, Bruneau & Stewart 2003;

Trujillo, Smith & Guaderrama 2011).

1.14.4 Cognitive Psychology

This is one of the branches of the psychology that concerned with mental

processes such as thinking, learning, perception and memory especially with

the internal event that happen between the sensory stimulation and overt

expression of behavior (Merriam-Webster, 2016). The cognitive

psychology will look into how our mental processing information will

influences the behavior.

1.14.5 Neuropsychological Assessment

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Neuropsychological assessment is a performance-based method to

assess cognitive functioning. This method is used to examine the cognitive

consequences of brain damage, brain disease, and severe mental illness (Harvey,

2012). Typically, neuropsychological assessment is performed with a battery

approach, which involves tests of a variety of cognitive ability areas, with more

than one test per ability area. These ability areas include skills such as memory,

attention, processing speed, reasoning, judgment, and problem-solving, spatial,

and language functions.

1.14.6 Memory

Memory is essential to all our lives. Memory is commonly described as

the process of maintaining information over time (Matlin, 2005). Without a

memory of the past we cannot operate in the present or think about the

future. We would not be able to remember what we did yesterday, what we

have done today or what we plan to do tomorrow. Without memory we could

not learn anything (Mcleod, 2007). Memory is when one’s draw the past

experience in order to use the information at present (Sternberg, 1999).

1.14.7 Attention

Attention is the concentration of awareness on some phenomenon to the

exclusion of other stimuli. Attention is the behavioral and cognitive process of

selectively concentrating on a discrete aspect of information, whether deemed

subjective or objective, while ignoring other perceivable information (Anderson

& John, 2004).

1.14.8 Visual Scanning

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Visual Scanning is the ability to actively find relevant information in our

surroundings quickly and efficiently (Cognifit, 2016). Examples of visual

scanning are spotting certain person in a crowded place such as at the party or

the other example was finding a specific location in a map. Slow speed and the

accuracy of the reaction and responses may indicate lack of visual scanning.

Example when driving, lack of visual scanning may cause an accident and

dangerous.

1.14.9 Mental Processing Speed

Mental processing speeds refer to ability to solve easy task in the

restricted amount of time (Doebler & Holling, 2015). Processing Speed is one

of the measures of cognitive efficiency or cognitive proficiency. It involves the

ability to automatically and fluently perform relatively easy or over-learned

cognitive tasks, especially when high mental efficiency is required.

1.14.10 Working Memory

Working memory refers to a brain system that provides temporary

storage and manipulation of the information necessary for such complex

cognitive tasks as language comprehension, learning, and reasoning (Baddeley,

1992). Often known as short-term memory, working memory is just like a brain

task. As the information coming into the brain, it will process and

simultaneously, storing it. It is important to learn, reasoning, and remember.

Example when doing a mathematical, one’s have to store the number temporary

while at the same time they have to solve the problem. In general, keeping the

information temporarily and process it at the same time is a working memory

(Psychology Glossary, 1998).

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CHAPTER 2

LITERATURE REVIEW

2.0 Introduction

In this chapter, theories and past studies that are relevant to the focus of the

present study are described and reviewed. The conceptual and theoretical frameworks

for the study are also explained.

2.1 Drug Addiction

The word drug was originality from a French word “drogue” which means “a

dry substance” and during that time, the dried herbs were widely used to prepare most

of the pharmaceuticals (Abadinsky, 2010).

Drug addiction is a chronic, often relapsing brain disease that causes

compulsive drug seeking and use, despite harmful consequences to the drug addict and

those around them. Drug addiction is a brain disease because the abuse of drugs leads

to changes in the structure and function of the brain. Drugs are chemicals that tap into

the brain's communication system and disrupt the way nerve cells normally send,

receive, and process information. There are at least two ways that drugs are able to do

this: by imitating the brain's natural chemical messengers, and/or over stimulating the

"reward circuit" of the brain. In 2014, the Malaysian National Anti-Drug Agency

(NADA) reported that there were 387,144 individuals registered as using drugs;

however, the true number of individuals using illicit psychoactive substances is likely

to be higher. Based on the NADA statistics, opioid use continues to dominate among

newly registered drug using individuals, with ~67% registered as using opioids and

~20% registered as using ATS (NADA 2015). Most individuals using opioids inject the

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drug; 25-30% of people who inject drugs (PWID) are infected with HIV; and injection

drug use accounts for 70% of HIV infections in Malaysia (101,672 registered HIV+

between 1986 and 2013).

Co-occurring ATS use among people who use opioids has also emerged as a

major problem in Malaysia. In recent surveys of people who inject heroin or other

opioids, 75% reported lifetime ATS use (and 21% reported injecting ATS), and lifetime

ATS use was significantly associated with HIV infection (Chawarski et al. 2012). Some

additional recently reported trends include rising rates of individuals under the age of

20 using drugs (NADA 2015; Hamudin 2015), growing attention on women who use

drugs (Mohd Nasarrudin et al. 2015; Rahman et al. 2015; Wickersham et al. 2016), and

continued research focus on relationships between substance use and infectious

diseases, particularly HIV and Hepatitis C (Bachireddy et al. 2011; Choo et al. 2015).

Addiction is associated with impairments in prefrontal cortex (PFC) dependent

cognitive functions; it is thought that these impairments promote compulsive drug use

and relapse (Volkow & Fowler, 2000). Opiate addicts and psychostimulant addicts

share some deficits in memory, cognitive flexibility and decision making (Bechara,

2005). Studies using laboratory animals have shown that repeated exposure to cocaine

or heroin impairs spatial memory (Tramullas, 2008). There are some fundamental

differences between opiates and psychostimulants. For example, cocaine and

amphetamine addicts are more impulsive and show more pronounced deficits in

attention and cognitive flexibility than heroin addicts (Lundqvist, 2005).

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2.2 Opioid

Opioids act by attaching to specific proteins called opioid receptors, which are

found in the brain, spinal cord, gastrointestinal tract, and other organs in the body.

When these drugs attach to their receptors, they reduce the perception of pain. Opioids

can also produce drowsiness, mental confusion, nausea, constipation, and, depending

upon the amount of drug taken, can depress respiration. Some people experience a

euphoric response to opioid medications, since these drugs also affect the brain regions

involved in reward. Heroin addiction is defined as a chronic relapsing condition that,

for many, is an unrelenting, lifelong illness with severe effects. This is particularly

relative to short life expectancies and high rates of morbidity Hser et al. (2004). Ninety

percent of the world’s heroin supply is directly from opium grown in Afghanistan.

Heroin that is produced from Afghan poppies is shipped worldwide (UNODC, 2010).

2.3 Amphetamine Type Stimulants

ATS or commonly known as ‘Ya Ba’ (crazy medicine) in Thailand and ‘pil

kuda’ or buah (street name) in Malaysia. Yaba is a combination of methamphetamine

(a powerfuland addictive stimulant) and caffeine. Yaba, which means crazy medicine

in Thai, is produced in Southeast and East Asia. The drug is popular in Asian

communities in the United States and increasingly is available at raves and techno

parties. Yaba is sold as tablets. These tablets are generally no larger than a pencil eraser.

They are brightly colored, usually reddish-orange or green. Yaba tablets typically bear

one of a variety of logos; R and WY are common logos. Yaba tablets typically are

consumed orally. The tablets sometimes are flavored like candy (grape, orange, or

vanilla). Another common method is called chasing the dragon. Users place the yaba

tablet on aluminum foil and heat it from below. As the tablet melts, vapors rise and are

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inhaled. The drug also may be administered by crushing the tablets into powder, which

is then snorted or mixed with a solvent and injected.

ATS or psycho-stimulants will cause an individual who taking it to feeling

euphoria, alertness, increased concentration and motor activity. They will increase

blood pressure and pulse rate and the long term use may cause effect such as violent

and irrational behavior and psychosis (Camí & Farré, 2003; Paci, 2008). Amphetamine

was derived from methamphetamine which have high lipid solubility comparing with

amphetamine and produce more intense effects on central nervous system (Barr et al.,

2006). In acute phase, amphetamine inhibit reuptake of dopamine, norepinephrine and

serotonin from membrane transporters and it will increase the level of these

neurotransmitter in the brain. This will give decrease of dopamine transporter which

associated with impaired neuropsychological functioning (Camí & Farré, 2003: Logan,

2002; Nordahl, Salo & Leamon, 2003; Scott et al., 2007).

2.4 Co-occurring Opioid and ATS Use

Co-occurring opioid and ATS use in Malaysia and Kelantan is increasing

although pharmacological effect on opioid and ATS in human body and brain are

different (Koob & Bloom 1988), the combination of an opioid and a psychostimulant

(e.g., amphetamine, methamphetamine, or cocaine) is also known as a “speedball. The

combination between Opioids and ATS may lead to addiction with overlapping effects

in reward circuitary system in the brain that is important for regulation of executive

function, motivation, affective or emotional response (Ersche & Sahakian 2007;

Trujillo, Smith & Guaderrama 2011). People who use this combination of drug report

that, it produces increased or unique pleasurable effects compared if taking a drug alone

or reduces the adverse effects of one of the drugs (e.g., reduces anxiety experienced